Subcellular kinetics of early trypsinogen activation in acute rodent pancreatitis.
To investigate the debated role of intracellular trypsinogen activation and its relation to lysosomal enzyme redistribution in the pathogenesis of acute pancreatitis, rats were infused with the cholecystokinin analog caerulein at 5 micrograms.kg-1.h-1 for intervals up to 3 h, and the changes were contrasted with those in animals receiving saline or 0.25 microgram.kg-1.h-1 caerulein. Saline or 0.25 microgram.kg-1.h-1 caerulein did not induce significant changes. In contrast, 5 micrograms.kg-1.h-1 caerulein caused significant hyperamylasemia and pancreatic edema within 30 min. Pancreatic content of trypsinogen activation peptide (TAP) increased continuously (significant within 15 min). TAP generation was predominantly located in the zymogen fraction during the first hour but expanded to other intracellular compartments thereafter. Cathepsin B activity in the zymogen compartment increased continuously throughout the experiments and correlated significantly with TAP generation in the same compartment. Total trypsinogen content increased to 143% with marked interstitial trypsinogen accumulation after 3 h. Supramaximal caerulein stimulation causes trypsinogen activation by 15 min that originates in the zymogen compartment and is associated with increasing cathepsin B activity in this subcellular compartment. However, a much larger pool of trypsinogen survives and accumulates in the extracellular space and may become critical in the evolution of necrotizing pancreatitis.
Mithöfer
K
K
Surgical Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Fernández-del Castillo
C
C
Rattner
D
D
Warshaw
A L
AL
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D002401:Cathepsin B / Q000378:metabolism; D002458:Cell Fractionation; D002108:Ceruletide; D004487:Edema; D004789:Enzyme Activation; D007700:Kinetics; D008297:Male; D009842:Oligopeptides / Q000378:metabolism*; D010195:Pancreatitis / Q000139:chemically induced / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000201:enzymology; D014362:Trypsinogen / Q000378:metabolism*
D009842:Oligopeptides; C080396:trypsinogen activation peptide; D002108:Ceruletide; D014362:Trypsinogen; D000681:Amylases; D002401:Cathepsin B